Humans and mice having dysfunctional mutations in the G-coupled receptor GPR54 have low gonadotropin levels and thus fail to undergo normal pubertal maturation. KiSS-1 gene products, known as kisspeptins, are thought to be the endogenous ligands for GPR54. KiSS-1 and GPR54 are expressed in areas of the forebrain that control reproduction and centrally-administered kisspeptins stimulate gonadotropin secretion in the rodent and primate. These observations suggest that activation of GPR54 is essential for the normal progression of pubertal development and the maintenance of reproductive function in the adult. The goal of this project is to elucidate the role of the KiSS-1 gene products (particularly Mestatin) and GPR54 in the neuroendocrine reproductive axis, focusing on their possible role in the negative and positive feedback control of gonadotropin secretion by sex steroids and in determining the onset of puberty. Elucidating the functional significance of Mestatin and GPR54 in the control of reproduction should provide further insight into the mechanisms responsible for idiopathic hypogonadotropic hypogonadism in humans and could provide scientific rationale for new therapies to treat precocious or delayed puberty and infertility.